JPH0627067B2 - Oral composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to an oral composition for preventing dental caries. More specifically, Streptococcus mutans
ptococcus mutans, hereinafter S. muta
The invention relates to an oral composition for preventing dental caries, which contains as an active ingredient tolmentic acid or a salt thereof having a specific antibacterial action against ns).

[Conventional technology]

It has been clarified that the cause of dental caries, which is an important disease in the field of oral surgery, is triggered by bacteria in the oral cavity. That is, S. mutans synthesizes a sticky polysaccharide from sucrose in food and drink, and S. Various microorganisms including mutans (lactic acid bacteria, Gram-negative bacteria, etc.) propagate and finally form bacterial plaque, which should be called a flora.

In addition, S. Bacteria such as mutans produce organic acids such as lactic acid from various sugars, and as a result of retention of these organic acids in dental plaque,
The enamel layer on the tooth surface is decalcified and caries occurs and progresses.

As is clear from the above-described mechanism of caries development, the three elements of dentinal oral bacteria (S. mutans), which are easily attacked by sucrose organic acids in food, are deeply involved in the development of caries. ing. Therefore, to prevent caries,
One of them needs to be removed. For this purpose, various caries preventive treatments have been tried. However, none of them has achieved a satisfactory effect.

Substituting all the sugars in food with other sweeteners is practically difficult, and the method of mixing fluoride with toothpaste containing fluoride or tap water to strengthen the tooth structure is more than its effect Is a problem, and it is never satisfactory.

On the other hand, S. In order to suppress the colonization of mutans in the oral cavity, bactericides such as chlorhexidine and various antibiotics have been studied (Shigeyuki Hamada, "How Can I Make Caries?" February 22, 1982, Iwanami Shinsho P125-13.
3).

However, bactericides such as chlorhexidine are highly toxic, have an unpleasant bitterness, and have the drawback of coloring teeth and oral mucosa. Moreover, bactericides and antibiotics are not suitable for long-term continuous use. Not only mutans but also indigenous bacteria in the oral cavity are indiscriminately killed to change the balance of indigenous bacterial flora and cause dental metastasis. And sometimes it even affects intestinal bacteria, often leading to unfavorable situations,
It is hard to say that it is a good caries preventive agent.

[Problems to be solved by the invention]

From the current situation, S. There is a demand for the development of a composition for the oral cavity which has a specific antibacterial action against mutans, and also has a plaque formation-preventing action.

[Means for solving problems]

We have found that S. As a result of various studies on the prevention of plaque formation, which has a specific antibacterial action against mutans, the formula [I] It was found that tolmentic acid or a salt thereof, which is a pentacyclic acidic triterpene compound represented by, is a compound suitable for this purpose, and completed the present invention.

That is, the present invention relates to S. What is provided is a composition for oral cavity for caries prevention, which contains tolmentinic acid represented by the formula [I] or a salt thereof as an active ingredient, which has a specific antibacterial effect against mutans and an effect of preventing plaque formation. Is.

Tormentic acid represented by the formula [I] is a naturally occurring substance, and it is contained in plants of the genus Gypsophila of the Labiatae family.

The inventors of the present invention have studied the genus Michaelis (Ls
tellipillum (miq.) Kitamura
An example of the preparation method in which tormentic acid is separated from et Murata) is as follows.

3.3 Kg of citrus cane leaves were cold-soaked and extracted several times with methanol, and the extract was concentrated to dryness. Chloroform was added to this substance to elute it by heating, and after cooling the solution again,
And a chloroform-soluble part was obtained. The same method was performed for ethyl acetate and n-butanol, and the operations were repeated to obtain an ethyl acetate and n-butanol-soluble portion. Chloroform and ethyl acetate soluble parts were combined and the solvent was distilled off to give 95 g.
Got the remnant of. This was subjected to silica gel column chromatography, and eluted with hexane, benzene, chloroform, and ethanol in order of increasing polarity.

The mixture obtained from the high polarity part was fractionated by the countercurrent distribution chromatography using the solvent system of chloroform / methanol / n-propyl alcohol / water and hexane / chloroform / methanol / water, and then Sephadex LH.
-20 (solvent system; chloroform: methanol = 1: 1)
And LOBER column (Merck) to obtain tormentic acid (109 mg).

The tolmentic acid used in the present invention can be obtained by the above-mentioned operation, but it may be derived from other raw materials or chemically synthesized products.

[Operation] Tormentic acid, which is an active ingredient of the oral cavity composition for preventing dental caries of the present invention, is used in oral bacteria S. It showed excellent results in antibacterial test against mutans and prevention of plaque formation. These effects useful for the prevention of dental caries will be described in detail by the following test examples.

Test Example (1) Antibacterial test A liquid culture medium dilution method was used. That is, tolmentic acid was dissolved in 3.7% brain heart infusion medium to a concentration of 100 μg / ml, and a 2-fold concentration dilution series was prepared in the same medium. 1 ml of each was dispensed into a test tube having a cotton plug, and autoclave sterilization was performed at 120 ° C. for 15 minutes. This was inoculated with 1 drop of the pre-cultured test bacterium,
Static culture was performed at ℃. After 2 days, the presence or absence of growth was visually determined and the minimum concentration (MIC) at which growth was inhibited was determined.

Strains used in the test 1. Streptococcus mutans MT8148
(Streptococcus mutans MT8
148) 2. Streptococcus mutans IFO 13
955 (Streptococcus mutans
IFO 13955) 3. Streptococcus mutans 6715 D
p (Streptococcus mutans 67
15 Dp) 4. Stahirococcus aureus IFO12732
(Staphylococcus aureus IF
O 12732) 5. Escherichia coli IFO 3545 (Esch
richia coli IFO 3545) 6. Pseudomonas aeruginosa IFO 308
0 (Pseudomonas aeruginosa
IFO 3080) Table 1 shows the results of the antibacterial test of the compound of formula [I] (tormentic acid), which is the active ingredient of the present invention, against the test strains. As is clear in the table, S.
It showed strong antibacterial activity against mutsans and had a MIC value of 50 μg / ml or less. The same pentacyclic triterpene compounds glycyrrhetinic acid and oleanolic acid S. The MICs against mutans 6715DP were 25 μg / ml and 400 μg / ml, respectively, and even the same pentacyclic triterpene compounds showed different antibacterial properties.

On the other hand, S. The MIC values for test bacteria other than mutans are all 100 μg / ml or more, and tolmentic acid as an active ingredient of the product of the present invention is S. It can be said that it is an ideal antibacterial agent for caries prevention that acts specifically on mutans and does not act on other bacteria resident in the oral cavity.

(2) Plaque formation test A model experiment was conducted by adhesion to the test tube wall. Lyophilized S. mutans 6715DP bacterium 0.5 mg
/ M 2 ml, 10% sucrose solution 0.2 ml, and test solution of each concentration 0.2 ml containing a solution of pH 6.8 37
The culture was performed at 18 ° C. for 18 hours by tilting at an angle of 30 ° and culturing in a static manner. After the completion of the culture, the test tube was slowly rotated, the liquid in the test tube was discarded, and the S. Mutans were evaluated visually.

Tormentic acid and oleanolic acid strongly inhibited adhesion at a concentration of 100 μg / ml, but glycyrrhetinic acid did not inhibit adhesion at all, and there was a difference between the compounds.

It was confirmed that tormentic acid showed a strong effect in both the antibacterial test and the plaque prevention test, and was effective in preventing dental caries.

(3) Acute toxicity test A group of 10 ddy mice was used, and in each group, dissolved and suspended tormentic acid was dissolved in saline with gum arabic at constant temperature (23 ± 1 ° C) and constant humidity (55 ± 5%). As a result of oral administration under the conditions of (1) and determination of LD50, the maximum dose for both males and females was 2 g / Kg or more.

Usage mode In order to use tolmentic acid represented by the formula [1] or a salt thereof as an oral composition, it is added to a conventional food after being formulated with an appropriate excipient or auxiliary agent. And can be applied intraorally. Preferred compositions include dentifrices, mouthwashes, coating solutions, troches, chewing gums, candies, drinks, dairy products and the like.

Raw materials such as excipients and auxiliaries used for producing these oral compositions may be appropriately selected from those usually used for this type of purpose depending on the dosage form, and are not particularly limited. Not something.

Fluoride such as sodium fluoride, phosphorus fluoride and sodium fluorophosphate can be added to this composition to further enhance its caries prevention effect. Sodium chloride can be added, preservatives, flavors and sweetness. Agents and colorants may be added appropriately.

The amount of tolmentinic acid or a salt thereof in the thus-prepared oral composition for preventing dental caries varies depending on the dosage form, but the concentration in use is 0.005% (weight / volume).
It is desirable that the content be the above.

〔Example〕

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

Example-1. Toothpaste Example-2. Containing agent Example-3. Lozenges Example-4. Chewing gum Example-5. Drink [Effect of the Invention] Tormentic acid or a salt thereof, which is an active ingredient of the oral cavity composition for preventing dental caries of the present invention, is S. cerevisiae of oral bacteria that produces dental plaque that causes dental caries. It is an extremely useful compound that shows a specific antibacterial action against mutans and does not affect other indigenous bacteria.

The oral composition of the present invention is extremely useful for preventing dental caries in sugar-containing beverages, especially infants who often have the opportunity to eat sweets, candy, etc., and of course contributes to the improvement of oral hygiene, and sugar is used as a raw material. The product of the present invention is considered to have an extremely high social contribution, since it greatly contributes to the industry in which it is used, such as sales promotion.

Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A23L 2/00 A A61K 7/16 7252-4C (72) Inventor Nagataka Yamazaki 9th, Akahori Shinmachi, Yokkaichi-shi, Mie No. 5 Taiyo Kagaku Co., Ltd. Examiner Tomoko Anabuki (56) References JP 6136213 (JP, A) JP 1-290619 (JP, A)

Claims (1)

[Claims] 1. A formula: Tormentic acid (Tormentic ac
id) or a salt thereof as an active ingredient for the prevention of dental caries.